Epigenetic gene silencing ubiquitously accompanies the development of prostate cancer (and other human cancers); reactivation of silenced genes has emerged as a rational treatment strategy. Epigenetic drugs, including small molecule inhibitors of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), and 5-meCpG-binding domain proteins (MBDs), trigger the reactivation of ~400 genes or more in cancer cells, and change the chromatin structure of many other genes in such a way as to facilitate expression in response to signaling and/or stress pathways. The new phenotypes induced in prostate cancer cells by epigenetic drugs expose unforeseen vulnerabilities to drugs targeting the products of genes that are now critical for survival in the reprogrammed state induced by the epigenetic drug. For this reason, the efficacy of epigenetic drugs in cancer may not be limited to reactivation of silenced tumor suppressor genes; rather, epigenetic drugs may also augment the activity of selected targeted drugs for cancer treatment by inducing synthetic lethality with epigenetic therapy (ISLET). An ongoing discovery research program has identified several promising combinations of DNMT inhibitors and targeted drugs that appear to exhibit properties of synthetic lethality; i.e., at concentrations where neither drug alone appears toxic to prostate cancer cells propagated in vitro, combined treatment exerts profound effects on prostate cancer cell survival. The goals of this Project are to undertake a structured preclinical assessment of these candidate combinations to prioritize the most promising for translation to clinical development for advanced prostate cancer.